rs2357322 and rs17726078 Contribute to Breast Cancer Risk by Regulating DLX2 Expression
Xin-Xin Zhang1, Hao Guo1, Hai-Yan Li1
1College of Life Sciences, Shaanxi Normal University, Xi'an Shaanxi, 710119, China, snnu.edu.cn.
The Breast Journal
|August 14, 2026
Summary
Two specific SNPs, rs2357322 and rs17726078, located near the DLX2 gene, may increase breast cancer risk by altering gene expression. These functional mutations appear to act as a regulatory attenuator for DLX2.
Area of Science:
- Genetics
- Molecular Biology
- Cancer Research
Background:
- Breast cancer is a prevalent female malignancy.
- Genome-wide association studies identified a single nucleotide polymorphism (SNP), rs2016394, in the DLX2 divergent transcript (DLX2-DT) intron associated with breast cancer risk.
- Three other SNPs (rs743605, rs2357322, rs17726078) are in strong linkage disequilibrium with rs2016394, but their functional roles remain unclear.
Purpose of the Study:
- To investigate the functional significance of SNPs associated with breast cancer risk in the DLX2 locus.
- To determine the mechanism by which these SNPs influence gene expression and potentially contribute to breast cancer development.
Main Methods:
- Luciferase assays were employed to assess the impact of SNPs on gene expression.
- Chromosome conformation capture (3C) was used to identify interactions between SNPs and regulatory elements.
- Chromatin immunoprecipitation (ChIP) was performed to detect transcription factor binding.
- CRISPR/Cas9 gene editing was utilized to knock out the cis-regulatory element containing the functional SNPs.
Main Results:
- SNPs rs2357322 and rs17726078 demonstrated allele-dependent differences in luciferase expression, indicating they are functional.
- Chromosome conformation capture revealed that DLX2 interacts with the cis-regulatory element containing rs2357322 and rs17726078.
- Transcription factor MYC binds to the region surrounding rs17726078.
- CRISPR/Cas9-mediated knockout of the cis-regulatory element significantly increased DLX2 mRNA and protein levels, alongside enhanced cell proliferation, colony formation, migration, and wound healing.
Conclusions:
- The SNPs rs2357322 and rs17726078 are functional and may regulate DLX2 expression.
- The identified cis-regulatory element acts as an attenuator, and its disruption leads to increased DLX2 expression and associated cellular phenotypes.
- These findings suggest that rs2357322 and rs17726078 may contribute to breast cancer risk by modulating DLX2 expression.
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